Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Consideraciones sobre los eventos trombóticos posteriores a la administración de la vacuna de AstraZeneca contra COVID-19 en Europa / Considerations for Thrombotic Events Following AstraZeneca COVID-19 Vaccine Administration in Europe

En las campañas de vacunación, como en la actual situación de COVID-19, es habitual que los países señalen posibles efectos adversos después de la vacunación. Esto no significa necesariamente que los eventos estén relacionados con la vacunación en sí, pero es necesario investigarlos. También muestra que el sistema de vigilancia funciona y que existen controles efectivos. La Organización Mundial de la Salud (OMS) está en contacto regular con la Agencia Europea de Medicamentos (EMA) y otras autoridades reguladoras del mundo para obtener la información más reciente sobre la seguridad de todas las vacunas para COVID-19.

Research Related Tumour Biopsies in Early-Phase Trials with Simultaneous Molecular Characterisation - a Single Unit Experience.

Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent.

Study Highlights the Need for Continuing Postapproval Drug Monitoring.

Follow-up on agents approved from 2001 to 2010 uncovered new safety concerns.

Tolerance and Withdrawal Issues with Sedatives in the Intensive Care Unit.

Prolonged use of sedative medications continues to be a concern for critical care practitioners, with potential adverse effects including tolerance and withdrawal. The amount of sedatives required in critically ill patients can be lessened and tolerance delayed with the use of pain and/or sedation scales to reach the desired effect. The current recommendation for prolonged sedation is to wean patients from the medications over several days to reduce the risk of drug withdrawal. It is important to identify patients at risk for iatrogenic withdrawal and create a treatment strategy.

[Technical specifications for intensive hospital safety monitoring of post-marketing Chinese medicine (draft version for comments)].

It is of vital significance to conduct active post-marketing surveillance of Chinese medicine, as an active response to laws, rules and guidelines issued by the China food and drug administration. The standards for technological specifications based on expert consensus have been drafted. These will provide technological support in evaluating adverse drug reactions (ADRs) or adverse drug events (ADEs). The technological specifications for post-marketing surveillance focus on two surveillance designs; one is a large sample registry study to explore general population ADR/ADE characteristics, the other is a nested case-control study to explore the characteristic and mechanisms of ADRs.

[Expert consensus post-marketing evaluation scheme to detect immunotoxicity of Chinese medicine in clinical populations (draft version for comments)].

Through consensus, establish a post-marketing scheme and the technical processes to evaluate Chinese medicine's immunotoxicity on a population, as well as its beneficial influences on the immune system. Provide regulations on the collection, storage and transportation of serum samples. This article applies to the post-marketing scientific evaluation of the immunotoxicity of parenterally administered, and for other ways of taking Chinese medicine.

[INR telemonitoring: efficacy and safety of a telemonitoring program in 453 patients]. / telemonitorização de INR: eficácia e segurança de um sistema de avaliação em 453 doentes.

INTRODUCTION: The INR analyses of patients taking oral anticoagulants brings great burden to healthcare professionals, overspending founds from the National Health Service (NHS) and loss of quality of life of patients who are forced to frequent hospital visits. It should not be surprising that the technology is at the forefront of health care nowadays and some projects have been developed in the area of anticoagulation for INR self-monitoring by telephone, mobile phone or internet. The aim of this study was to assess the efficacy and safety of an INR telemonitoring system that was implemented in our hospital in 2006. METHODS: A prospective, observational study of 453 patients who were included in this telemonitoring system from 2006 until late November 2010. The communication between patients and health professionals was done via mobile phone messages in a standardized and codified system that included information about maintenance or modification of therapy and the date of the next evaluation. When necessary the patient could send a request for help through a code for that purpose. In the studied population the following parameters were evaluated: withdrawal of the telemonitoring project, need for change of anticoagulant dose, requests for clarification by the patient, hospitalization for bleeding complications and INR > 10. RESULTS: In our study population 53% were female, mean age = 57 +/- 16 years. The percentage of INR values within the therapeutic range was 83%. There were no dropouts of the telemonitoring project. The percentage of patients with major and minor bleeding complications during follow-up was 0.4% and 0.2% respectively. CONCLUSIONS: The telemonitoring system proves safe and effective remote monitoring of INR analysis, allowing efficient monitoring of INR with low prevalence of major or minor bleeding.

Bipolaridad: monitoreo terapéutico de drogas antiepilépticas / Bipolarity: Therapeutic monitoring of antiepileptic drugs

Objetivo: Revisión bibliográfica del monitoreo de los fármacos utilizados en el tratamiento de la bipolaridad y las recomendaciones que de allí se derivan para su aplicación en el ámbito de la asistencia clínica de pacientes con patología bipolar. Método: Búsqueda en medline y medscape desde 1998 hasta mayo 2011 de los siguientes términos: monitoreo, valproato, lamotrigina, carbamacepina, gabapentina, topiramato, antiepilépticos, trastornos bipolares, interacciones farmacológicas y eventos adversos. Fueron consultadas las guías de tratamiento (CANMAT: Canadian Network for Mood and Anxiety Treatments, update 2009), aprobaciones de la FDA (Food and Drug Administation, EEUU) y recomendaciones de la Asociación Americana de Psiquiatría (APA). Resultados: Los fármacos para los cuales se halló evidencia documentada en bipolaridad, hasta el momento son: valproato, lamotrigina y carbamacepina; no habiendo evidencia que avale el uso de gabapentina o topiramato. Los principales eventos adversos de los antiepilépticos son los del sistema nervioso; requieren evaluación clínica, ya que carecen de un laboratorio específico. Constituye una excepción la hiperamoniemia producida por valproato que puede medirse en el laboratorio y ser causa de encefalopatía o asociarse, con más frecuencia, a trastornos cognitivos. El monitoreo de valproato está recomendado, así como el de amonio. El monitoreo de lamotrigina podría ser útil. La titulación debe ser lenta, para disminuir riesgo de rash potencialmente fatal. Considerar el inicio del tratamiento con monodroga. Se recomienda el monitoreo de carbamacepina y en caso de polifarmacia: el monitoreo del epóxido de carbamacepina. En los tres fármacos considerar interacciones y la posibilidad de toxicidad aún dentro del rango terapéutico

Objective: Literature review of monitoring of AEDs used in the treatment of bipolarity and the recommendations arising from there for use in the field of clinical care of patients with bipolar disease. Method: Search Medscape and medline from 1998 to May 2011 of the following terms: monitoring, valproate, lamotrigine, carbamazepine, gabapentin, topiramate, antiepileptics, bipolar disorders, drug interactions and adverse events. having consulted in addition to treatment guidelines Canadian Network for Mood and Anxiety Treatments, update 2009 (CANMAT), approvals of the Food and Drug Administration, USA (FDA) and recommendations of the American Psychiatric Association (APA). Results: Drugs with documented evidence for use in bipolar disorder are: valproate, lamotrigine and carbamazepine, there being no evidence to support the use of gabapentin or topiramate. It is important to consider that the main adverse effects of antiepileptic drugs (AEDs) develop in the Nervous System. These symptoms require clinical evaluation, since they lack a specific laboratory, except hyperammonemia: a parameter measurable in the laboratory, produced by valproate that is associated with encephalopathy and cognitive disorders. Valproate monitoring is recommended, as well as ammonium. Monitoring of lamotrigine may be useful. The titration should be slow always, to avoid risk of potentially fatal rash. Consider, where possible, the beginning of treatment with single drug. Carbamazepine monitoring is recommended and in case of polypharmacey: the monitoring of carbamazepine epoxide becomes useful. In all cases should be evaluated possible interactions and their mechanisms to have in mind the possibility of toxicity symptoms even with plasma dosages within the therapeutic range

A reliable and safe method of collecting blood samples from implantable central venous catheters for determination of plasma gentamicin concentrations.

STUDY OBJECTIVE: To evaluate the extent of agreement between plasma gentamicin concentrations determined from samples collected by using implantable subcutaneous central venous catheters (ports) with the push-pull method and those collected by finger lancet punctures in children with febrile neutropenia. DESIGN: Prospective, randomized study. SETTING: University-affiliated, tertiary care hospital. PATIENTS: Sixty-two children with cancer who had single- or double-lumen ports and who received gentamicin for treatment of febrile neutropenia between February 2008 and October 2009. INTERVENTION: One blood sample was collected from the port by using the push-pull method at the same time one blood sample was collected by finger lancet puncture for determination of plasma gentamicin concentrations. MEASUREMENTS AND MAIN RESULTS: Forty-four pairs of samples were available for assessment of agreement, and 43 were available for pharmacokinetic analysis. Agreement between plasma gentamicin concentrations determined from blood samples from ports and finger lancet punctures was assessed by the intraclass correlation coefficient (ICC), Bland-Altman analysis, and comparison of simulated dosage adjustments. Changes in port patency were monitored for 1 week after port sampling. Differences in simulated dosage adjustments calculated by using either the port or finger lancet puncture samples that differed by greater than 20% were considered clinically significant. Agreement between the 44 finger lancet puncture and port sample pairs was excellent (ICC 0.991, 95% confidence interval 0.984-0.995). Port plasma gentamicin concentrations were 4.7% lower than those concentrations determined in blood from finger lancet punctures. The observed limits of agreement ranged from -20.5% to 11%. Differences in dosage adjustments calculated by using port and finger lancet puncture plasma gentamicin concentrations were not clinically significant in 38 (88%) of 43 cases. No changes in port patency were observed in the week after port sampling. CONCLUSION: The push-pull method of blood sampling is a reliable and safe option for determining plasma gentamicin concentrations in children with ports.

In vitro and in vivo evaluation of anti-inflammatory agents using nanoengineered alginate carriers: towards localized implant inflammation suppression.

The aim of this research was to develop nanoengineered alginate microspheres for localized delivery of anti-inflammatory drugs (dexamethasone and diclofenac sodium) for implantable "Smart tattoo" glucose biosensor used for continuous glucose monitoring. The formulation was prepared and characterized for in vitro drug release from uncoated and polyelectrolyte-coated microparticles. Biocompatibility was then tested using L929 cell-line; pilot in vivo studies with Sprague-Dawley (SD) rat subjects were performed to test the suppression of inflammation and fibrosis associated with implantation and was analyzed using standard hematoxylin and eosin staining method. The drug-loaded microspheres were able to deliver the drug for 30 days at a controlled rate with zero-order kinetics. The layer-by-layer self-assembly technique was used to effectively limit the burst release of drug from the matrix. Cell culture studies prove that the material are not cytotoxic and showed acceptable >80% cell viability in all the tested samples. In vivo studies show that both drugs were successful in controlling the implant/tissue interface by suppressing inflammation at the implant site. It was clearly evident that the combined approach of drug loaded carriers along with implanted biosensor shows promise in improving sensor biocompatibility and functionality. Thus, suggesting potential application of alginate microspheres as "smart-tattoo" glucose sensors.

Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease.

Busulfan influences engraftment and toxicities during hematopoietic stem cell transplantation (HSCT). We report our single-institution experience of targeted busulfan therapy for myeloablative, matched sibling donor (MSD) HSCT for sickle cell disease (SCD) and assess the relationships of busulfan levels to engraftment and toxicities. Twenty-seven patients with SCD underwent MSD HSCT from 1993 to 2007, 25 with busulfan measurements. The conditioning regimen was busulfan (initial dose 0.875 mg/kg for 16 doses), CY and antithymocyte globulin. Busulfan area under curve (AUC) was determined with the first dose, and dose adjustments were made to target the desired AUC range. Median AUC was 963 µmol min/L (range 780-1305 µmol min/L). Engraftment occurred in all cases: 21 (84%) full donor chimerism (> 95% donor cells), 4 (16%) partial donor chimerism. Hepatic veno-occlusive disease (VOD) occurred in 8 (32%) patients. Lower AUC was seen with partial donor chimerism (862 ± 73 µmol min/L) versus full donor chimerism (AUC 1018 ± 122 µmol min/L) (P = 0.022). VOD was not associated with busulfan AUC (P = 0.153). Of 25 patients, 24 survived with median follow-up of 4.9 years. Our experience shows that targeting busulfan AUC above the range used in previous multicenter trials appears safe and may contribute to sustained engraftment in SCD.

Women's experiences of participating in the Magpie Trial: a postal survey in the United Kingdom.

BACKGROUND: The Magpie Trial compared magnesium sulfate with placebo for women with preeclampsia. The objective of this study was to explore women's views and experiences of participating in the Magpie Trial in the United Kingdom. METHODS: Postal questionnaires were sent to 771 women participants in the Magpie Trial to assess long-term health of UK women and children. The questionnaire included three questions exploring women's experience of participating in the trial: (a) If time suddenly went backward, and you had to do it all over again, would you agree to participate in the Magpie Trial? (b) Please tell us if there was anything about the Magpie Trial that you think could have been done better; and (c) Please tell us if there was anything about the Magpie Trial, or your experience of joining the trial, that you think was particularly good. RESULTS: Overall, 619 of the 771 women who were sent questionnaires returned them. In response to the three questions: (a) 58 percent (356) of women responded "definitely yes," 27 percent (169) "probably yes," 4 percent (23) "probably no," 5 percent (33) "definitely no," and 5 percent (34) "not sure." No clear evidence was shown of a relationship with allocated treatment, although women who responded "probably or definitely no" were more likely to have had side effects from trial treatment. (b) Although 44 percent of women stated that nothing could have been done better, free text suggestions related to content of recruitment information, and its timing, and wanting to know treatment allocation and trial results. c) Women were generally extremely positive about being followed up and receiving trial results. CONCLUSIONS: Women were largely positive about participation in the trial and its follow-up, but still reported ways they believed the study could have been improved, such as more information, given earlier, which also has implications for clinical care.